Salagen 5 mg Film Coated Tablets - (emc)

Salagen film-coated tablets are white, round biconvex tablets, marked “SAL” on one side and “5” on the other side. 4. Clinical particulars. 4.1 Therapeutic ... Skiptomaincontent Salagen5mgFilmCoatedTablets Backtotop MerusLabsLuxcoIIS.àR.L.contactdetails Activeingredient pilocarpinehydrochloride LegalCategory POM:Prescriptiononlymedicine ATCcode N07AX01 Findsimilarproducts ReportSideEffect RelatedMedicines Sameactiveingredients Samecompany Bookmark Email Lastupdatedonemc:04Jun2019 Viewchanges Print Showtableofcontents Hidetableofcontents 1.Nameofthemedicinalproduct2.Qualitativeandquantitativecomposition3.Pharmaceuticalform4.Clinicalparticulars4.1Therapeuticindications4.2Posologyandmethodofadministration4.3Contraindications4.4Specialwarningsandprecautionsforuse4.5Interactionwithothermedicinalproductsandotherformsofinteraction4.6Fertility,pregnancyandlactation4.7Effectsonabilitytodriveandusemachines4.8Undesirableeffects4.9Overdose5.Pharmacologicalproperties5.1Pharmacodynamicproperties5.2Pharmacokineticproperties5.3Preclinicalsafetydata6.Pharmaceuticalparticulars6.1Listofexcipients6.2Incompatibilities6.3Shelflife6.4Specialprecautionsforstorage6.5Natureandcontentsofcontainer6.6Specialprecautionsfordisposalandotherhandling7.Marketingauthorisationholder8.Marketingauthorisationnumber(s)9.Dateoffirstauthorisation/renewaloftheauthorisation10.Dateofrevisionofthetext Thisinformationisintendedforusebyhealthprofessionals 1.Nameofthemedicinalproduct Salagen®5mgfilm-coatedtablets 2.Qualitativeandquantitativecomposition Eachfilm-coatedtabletcontains5mgofpilocarpinehydrochloride. Forafulllistofexcipients,seesection6.1. 3.Pharmaceuticalform Film-coatedtablet Salagenfilm-coatedtabletsarewhite,roundbiconvextablets,marked“SAL”ononesideand“5”ontheotherside. 4.Clinicalparticulars 4.1Therapeuticindications •Alleviationofsymptomsofsalivaryglandhypofunctioninpatientswithseverexerostomiafollowingirradiationforheadandneckcancer. •TreatmentofsymptomsofdrymouthanddryeyesinpatientswithSjögren'ssyndrome. 4.2Posologyandmethodofadministration Posology •Forheadandneckcancerpatients: Therecommendedinitialdoseforadultsis1tabletof5mgthreetimesdaily.Themaximaltherapeuticeffectisnormallyobtainedafter4to8weeksoftherapy.Forpatientswhohavenotrespondedsufficientlyafter4weeksandwhotoleratethedoseof5mgthreetimesdaily,dosesofuptoamaximumof30mgdailymaybeconsidered.However,higherdailydosesareprobablyaccompaniedbyanincreaseindrug-relatedadverseeffects.Therapyshouldbediscontinuedifnoimprovementinxerostomiaisnotedafter2to3monthsoftherapy. •ForSjögren'ssyndromepatients: Therecommendeddoseforadultsisonetabletof5mgfourtimesdaily.Forpatientswhohavenotrespondedsufficientlytoadosageof5mgfourtimesdailyandwhotoleratethisdosage,increasingthedoseuptoamaximumof30mgdaily,dividedovertheday,maybeconsidered.Therapyshouldbediscontinuedifnoimprovementinthesymptomsofdrymouthanddryeyesisnotedafter2to3months. SpecialPopulations Useintheelderly: Thereisnoevidencetosuggestthatdosageshouldbedifferentintheelderly. Paediatricpopulation: Thesafetyandefficacyofthismedicinalproductinthepaediatricpopulationhavenotbeenestablished. Useinpatientswithimpairedhepaticfunction: Patientswithmoderateandseverecirrhosisshouldstarttreatmentonareduceddailydosageschedule.Dependingonthesafetyandtolerability,thedosagemaygraduallybeincreasedtothenormaldailydosagescheduleof5mgthreetimesaday. Useinpatientswithimpairedrenalfunction: Insufficientinformationisavailabletodeterminetheimportanceofrenalexcretionofpilocarpineanditsmetabolitessoastorecommenddosageadjustmentsforpatientswithrenalinsufficiency(seeSection4.4andSection5.2). Methodofadministration •Forheadandneckcancerpatients: Tabletsshouldbetakenwithaglassofwaterduringordirectlyaftermeals.Thelasttabletshouldalwaysbetakeninconjunctionwiththeeveningmeal. •ForSjögren'ssyndromepatients: Tabletsshouldbetakenwithaglassofwateratmealtimesandbedtime. 4.3Contraindications Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1. Salageniscontraindicatedinpatientswithclinicallysignificant,uncontrolledcardiorenaldisease,uncontrolledasthmaandotherchronicdiseaseatriskforcholinergicagonists. Salageniscontraindicatedincaseswheremiosisisundesirable,suchasinacuteiritis. 4.4Specialwarningsandprecautionsforuse Cautionshouldbeexercisedinpatientswhoareknownorexpectedtosweatexcessivelyandwhocannotdrinkenoughliquids,sincedehydrationcoulddevelop. Pilocarpinehasbeenreportedtoincreaseairwayresistanceinasthmaticpatients.Also,patientswithsignificantcardiovasculardiseasemaybeunabletocompensatefortransientchangesinhaemodynamicsorheartrhythminducedbypilocarpine.Therefore,Salagenshouldbeadministeredtopatientswithcontrolledasthmaorsignificantcardiovasculardiseaseonlyifthebenefitsarebelievedtooutweightherisks,andunderclosemedicalsupervision. Salagenshouldbeusedwithcautioninpatientswiththefollowingillnesses/pathologies: -Chronicbronchitisand/orchronicobstructivepulmonarydisease.Thesepatientshavehyperactiveairwaysandmayexperienceadverseeffectsduetoincreasedbronchialsmoothmuscletoneandincreasedbronchialsecretions. -Knownorsuspectedcholelithiasisorbiliarytractdisease.Contractionsofthegallbladderorbiliarysmoothmusclecouldprecipitatecomplicationsincludingcholecystitis,cholangitisandbiliaryobstruction. -Pepticulceration,duetotheriskofincreasedacidsecretion. -Underlyingcognitiveorpsychiatricdisturbances.Cholinergicagonists,likepilocarpinehydrochloride,mayhavedose-relatedcentralnervoussystemeffects. -CautionshouldbeexercisedwhenadministeringSalageninpatientswithrenalinsufficiency. -Pilocarpinemayincreaseureteralsmoothmuscletoneandcouldtheoreticallyprecipitaterenalcolic(or“ureteralreflux”),particularlyinpatientswithnephrolithiasis. -Salagenshouldbeadministeredwithcautioninpatientswithnarrow-angleglaucoma. 4.5Interactionwithothermedicinalproductsandotherformsofinteraction Salagenshouldbeadministeredwithcautiontopatientstakingbetaadrenergicantagonistsbecauseofthepossibilityofconductiondisturbances. ConcurrentadministrationofSalagenanddrugswithparasympathomimeticeffectsisexpectedtoresultinadditivepharmacologiceffects. Pilocarpinemightantagonisetheanticholinergiceffectsofotherdrugsusedconcomitantly(e.g.atropine,inhaledipratropium). Whilenoformaldruginteractionstudieshavebeenperformed,thefollowingconcomitantdrugswereusedinatleast10%ofpatientsineitherorbothSjögren'sefficacystudies:acetylsalicylicacid,artificialtears,calcium,conjugatedestrogens,hydroxychloroquinesulfate,ibuprofen,levothyroxinesodium,medroxyprogesteroneacetate,methotrexate,multivitamins,naproxen,omeprazole,paracetamol,andprednisone.Therewerenoreportsofdrugtoxicitiesduringeitherefficacystudy. IninvitrostudiespilocarpinehasbeenfoundtobeaninhibitorofCYP2A6.InvivoinhibitionandthereforeaninteractionwithCYP2A6substrates(e.g.irbesartan,coumarin)cannotberuledout(seesection5.2). 4.6Fertility,pregnancyandlactation Pregnancy: Thesafetyofthismedicinalproductforuseinhumanpregnancyhasnotbeenestablished.Therearenoknownhumandatafortheeffectsofpilocarpineonfoetalsurvivalanddevelopment.Studiesinanimalshaveshownreproductivetoxicity(seesection5.3). Salagenisnotrecommendedduringpregnancyandinwomenofchildbearingpotentialnotusingcontraception. Breastfeeding: Animalstudieshaveshownexcretionofpilocarpineinmilkatconcentrationssimilartothoseseeninplasma.Itisnotknownwhetherpilocarpineissecretedinhumanmilk.Adecisionmustbemadewhethertodiscontinuebreast-feedingortodiscontinuefromSalagentherapy. Fertility: Theeffectsofpilocarpineonmaleandfemalefertilityarenotknown.Studiesinmice,ratsanddogshaveshownadverseeffectsonspermatogenesis.Astudyinratshasalsoindicatedapossibleimpairmentoffemalefertility(seesection5.3).Thesafetymarginfortheeffectsonfertilityisunknown. Basedontheresultsofavailablestudiesinanimals(seesection5.3)asaprecautionarymeaure,Salagentabletsshouldbeadministeredtoindividualhumanmaleswhoareattemptingtofatherachild,only,iftheexpectedbenefitjustifiespotentialimpairmentoffertility. 4.7Effectsonabilitytodriveandusemachines PatientswhoexperiencedizzinessduringSalagentreatmentshouldbeadvisednottodriveoroperatemachinery. Pilocarpinehasbeenreportedtocauseimpairmentofdepthperceptionandvisualblurring.Thelattermayresultindecreasedvisualacuity,especiallyatnightandinpatientswithcentrallenschanges.Ifthisoccurs,patientsshouldbeadvisednottodriveatnightorperformhazardousactivitiesinreducedlighting. 4.8Undesirableeffects MostoftheadverseexperiencesobservedduringSalagentreatmentwereaconsequenceofexaggeratedparasympatheticstimulation.Theseadverseexperiencesweredose-dependentandusuallymildandself-limited.However,severeadverseexperiencesmightoccasionallyoccurandthereforecarefulmonitoringofthepatientisrecommended. Incontrolledclinicaltrialsthefollowingadversereactionswereobserved: Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness. Verycommon(≥1/10);common(≥1/100,<1/10);uncommon(≥1/1,000,<1/100);rare(≥1/10,000,<1/1,000);veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata). Nervoussystemdisorders Verycommon:headache Common:dizziness Eyedisorders Common:lacrimation;blurredvision;abnormalvision;conjunctivitis;eyepain Cardiacdisorders Common:flushing(vasodilatation);hypertension;palpitations Respiratory,thoracicandmediastinaldisorders Common:rhinitis Gastrointestinaldisorders Common:dyspepsia;diarrhoea;abdominalpain;nausea,vomiting;constipation,increasedsalivation Uncommon:flatulence Skinandsubcutaneoustissuedisorders Verycommon:sweating Common:allergicreactions,includingrash,pruritus Renalandurinarydisorders Verycommon:increasedurinaryfrequency Uncommon:urinaryurgency Generaldisordersandadministrationsiteconditions Verycommon:flusyndrome Common:asthenia,chills ThereisnoindicationofadifferencebetweenolderandyoungerpatientsreceivingSalagenasregardsreportingadverseexperiences,exceptfordizziness,whichwasreportedsignificantlymoreoftenbypatientsagedover65years. Thefollowingadverseeffects,whichareduetotheintrinsicpharmacologicalpropertiesofpilocarpine,havebeenpublishedinthemedicalliterature:respiratorydistress,gastro-intestinalspasm,atrioventricularblock,tachycardia,bradycardia,cardiacarrhythmia,hypotension,shock,tremors,andmentalstatuschangesincludingmemoryloss,hallucinations,labilityofaffect,confusion,agitation. Reportingofsuspectedadversereactions Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinuedmonitoringofthebenefit/riskbalanceofthemedicinalproduct.HealthcareprofessionalsareaskedtoreportanysuspectedadversereactionsviatheYellowCardSchemeat:www.mhra.gov.uk/yellowcard. 4.9Overdose Overdosemayleadtoa'cholinergiccrisis'characterisedbybothmuscarinicandnicotiniceffects. Signsofoverdoseduetomuscariniceffectsmayincludeabdominalcramps,diarrhoea,nauseaandvomiting,involuntarydefecationandurination,sweating,salivation,increasedbronchialsecretions,miosis,bradycardiaandhypotension. Nicotiniceffectsmayincludeinvoluntarytwitching,fasciculationsandgeneralisedweakness. Parenteralatropinemaybeusedasanantidotetothemuscariniceffects.Supportivetreatmentshouldbegivenasrequired;artificialrespirationshouldbeinstitutedifrespiratorydepressionissevere. 5.Pharmacologicalproperties 5.1Pharmacodynamicproperties Pharmacotherapeuticgroup:Parasympathominetic,ATCcode:N07AX01. Mechanismofaction Pilocarpineisacholinergicparasympathomimeticagentexertingabroadspectrumofpharmacologiceffectswithpredominantmuscarinicaction.Pilocarpine,inappropriatedosage,canincreasesecretionbyexocrineglandssuchasthesweat,salivary,lacrimal,gastric,pancreaticandintestinalglandsandthemucouscellsoftherespiratorytract. Pharmacodynamiceffects Dose-relatedsmoothmusclestimulationoftheintestinaltractmaycauseincreasedtone,increasedmotility,spasmandtenesmus.Bronchialsmoothmuscletonemayincrease.Thetoneandmotilityofurinarytract,gallbladderandbiliaryductsmoothmusclemaybeenhanced. Pilocarpinemayhaveparadoxicaleffectsonthecardiovascularsystem.Theexpectedeffectofamuscarinicagonistisvasodepression,butadministrationofpilocarpinemayproducehypertensionafterabriefepisodeofhypotension.Bradycardiaandtachycardiahavebothbeenreportedwithuseofpilocarpine. Clinicalefficacyandsafety Inastudyinhealthymalevolunteersanincreaseinsalivaryflowfollowingsingle5and10mgdosesofSalagenwasnoted20minutesafteradministration,andlastedfor3to5hourswithapeakat1hour. •Forheadandneckcancerpatients: Intwo12-weekrandomised,double-blindplacebo-controlledclinicalstudiesinpatientswithxerostomiaresultingfromirradiationtotheheadandneckforcancer,Salagentreatmentreduceddrynessofthemouth;inoneofthesestudiesthisdidnotoccuruntilafter12weeksoftreatment.Also,Salagentreatmentincreasedsalivaryflow.Thegreatestimprovementindrynesswasnotedinpatientswithnomeasurablesalivaryflowatbaseline. Inbothstudies,somepatientsnotedimprovementintheoverallconditionofxerostomia,speakingwithoutdrinkingliquids,andmouthcomfort,andtherewasreduceduseofconcomitanttherapy(i.e.artificialsaliva)fordrymouth. •ForSjögren'ssyndromepatients: Twoseparate12-weekrandomised,double-blindplacebo-controlledclinicalstudieswereconductedinpatientsdiagnosedwithprimaryorsecondarySjögren'ssyndrome.Inbothstudies,themajorityofpatientsbestfittheEuropeancriteriaforhavingprimarySjögren'ssyndrome.TheabilityofSalagentostimulatesalivaproductionwasassessed.Relativetoplacebo,anincreaseintheamountofsalivabeingproducedwasobservedfollowingthefirstdoseandwasmaintainedthroughoutthedurationofthetrialsinanapproximatedoseresponsefashion. Comparedtoplaceboastatisticallysignificantglobalimprovementforbothdrymouthanddryeyeswasobserved. EfficacyofSalagenhasnotbeenestablishedinpatientswiththeSjögren'ssyndromeduringlongtermtreatment(>12weeks). 5.2Pharmacokineticproperties Absorption Inamultiple-dosepharmacokineticstudyinvolunteersgiven5or10mgofpilocarpinehydrochloridethreetimesdailyfortwodays,theTmaxafterthefinaldosewasapproximately1hour,theeliminationT½wasapproximately1hour,andthemeanCmaxwere15ng/mland41ng/mlforthe5and10mgdoses,respectively. Whentakenwithahigh-fatmeal,therewasadecreaseintherateofabsorptionofpilocarpinefromSalagentablets.MeanTmaxwere1.47and0.87hoursandmeanCmaxwere51.8and59.2ng/mlforfedandfastedmalevolunteers,respectively. Distribution Pilocarpineisextensivelydistributedwithanapparentvolumeofdistributionof2.1L/kg.Datafromanimalstudiesindicatesthatpilocarpineisdistributedintobreastmilkatconcentrationssimilartoplasma.Preclinicaldataalsosuggeststhatpilocarpinecancrossthebloodbrainbarrierathighdose.Pilocarpinedoesnotbindtoplasmaproteins. Metabolism PilocarpineisprimarilymetabolizedbyCYP2A6andhasdemonstratedacapacitytoinhibitCYP2A6invitro.Serumesterasesarealsoinvolvedinthebiotransformationofpilocarpinetopilocarpicacid. Elimination Approximately35%ofdoseiseliminatedas3-hydroxypilocarpineinurineand20%ofdoseisexcretedunchangedintheurine.Meaneliminationhalf-livesforpilocarpineis0.76and1.35hoursafterrepeatedoraldosesof5and10mgofpilocarpinehydrochloride,respectively. Elderly PilocarpineAUCvaluesinelderlymalevolunteerswerecomparabletothoseinyoungermales.InasmallnumberofhealthyelderlyfemalevolunteersthemeanAUCwasapproximatelytwicethatofelderlyandyoungmalevolunteersduetoreducedvolumesofdistribution.However,theobserveddifferenceinpharmacokineticswasnotreflectedintheincidenceofadverseeventsbetweenyoungandelderlyfemalepatients.Nodosageadjustmentisrequiredinelderlysubjects. Renalimpairment Apharmacokineticstudyofpilocarpineinpatientswithmildandmoderatelyimpairedrenalfunctionshowedthattherewasnosignificantdifferenceinclearanceandexposurecomparedwithsubjectswithnormalrenalfunction. 5.3Preclinicalsafetydata Genotoxicityandcarcinogenicity: Pilocarpinedidnotindicateagenotoxicpotentialinaseriesofinvitroandinvivogenotoxicitystudies.InlifetimeoralcarcinogenicitystudiesinrodentsPilocarpinedidnotcauseanincreaseintumourincidenceinmice,butwasassociatedwithanincreasedincidenceinbenignpheochromocytomasinratsat>15timestheexposureatthemaximumrecommendedhumandoseandthereforenotconsideredrelevanttoclinicaluse.Preclinicaldatarevealednospecialhazardforhumansbasedonconventionalstudiesofgenotoxicityandcarcinogenicpotential. Fertility Animalstudieshaveshownadverseeffectsonthemalereproductivetractfollowingchronicexposurestopilocarpine.Impairedspermatogenesiswasobservedinratsanddogsfollowing28-dayand6-monthoralexposuresrespectively.Histopathologicalchangeswerealsoobservedinthetestesandbulbourethralglandsofmicegivenpilocarpinefor2years. Thesafetymarginfortheeffectsinhumansisunknown.However,bodysurfacearea[mg/m2]comparisonssuggestthatthelowestdoseassociatedwithimpairedfertility,(3mg/kg/dayinthedog),isapproximately3timesthemaximumrecommendedhumandose,thereforearisktohumanscannotberuledout.Astudyinratshasalsoindicatedapossibleimpairmentoffemalefertility(seesection4.6). Reproductivetoxicity: Studiesinpregnantratsshowedtreatment-relatedreductionsinthemeanfetalbodyweightandincreasesintheincidenceofskeletalvariations[atapproximately26timesthemaximumrecommendeddosefora50kghuman(basedoncomparisonsofbodysurfacearea[mg/m2].Theseeffectsoccurredatdosesthatwerematernallytoxic.Therewasnoevidenceofateratogeniceffectintheanimalstudies.Treatmentrelatedincreasesintheincidenceofstillbirthswithdecreasedneonatalsurvivalandreducedmeanbodyweightofpupswereobservedinpre-andpostnatalstudies.Asafetymarginfortheseeffectscannotbecalculated.However,bodysurfacearea[mg/m2]comparisonssuggestthattheeffectoccurredatapproximately5timesthemaximumrecommendeddosefora50kghuman.Theclinicalrelevanceofthesefindingsisunknown(seesection4.6). 6.Pharmaceuticalparticulars 6.1Listofexcipients Binder/diluent: Microcrystallinecellulose Acidifier/lubricant: Stearicacid Filmcoating: OpadryWhite,OY-7300,containinghypromellose,macrogol400andtitaniumdioxide(E171) Polish: Carnaubawax 6.2Incompatibilities Notapplicable 6.3Shelflife 3years 6.4Specialprecautionsforstorage Donotstoreabove25°C. Storeintheoriginalpackageinordertoprotectfromlightandmoisture. 6.5Natureandcontentsofcontainer SalagenisdistributedforsaleinperforatedAl/PVC/PVDCblisters. Eachblistercontains14or21tablets. Acartoncontains1,2or6ofthe14-tabletblisters,or1or4ofthe21-tabletblisters. Notallpacksizesmaybemarketed. 6.6Specialprecautionsfordisposalandotherhandling Nospecialrequirements. 7.Marketingauthorisationholder NorginePharmaceuticalsLimited, NorgineHouse,WidewaterPlace, MoorhallRoad,Harefield, Uxbridge,UB96NS,UK. 8.Marketingauthorisationnumber(s) PL20011/0069 9.Dateoffirstauthorisation/renewaloftheauthorisation Dateoffirstauthorisation: 01July2001 Dateoflastrenewal: 01July2006 10.Dateofrevisionofthetext May19 LEGALCATEGORY POM ReportSideEffect RelatedMedicines Sameactiveingredients Samecompany Bookmark Email Lastupdatedonemc:04Jun2019 Viewchanges Print Companycontactdetails MerusLabsLuxcoIIS.àR.L. 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